Niemann-Pick Disease Type A
Niemann-Pick disease type A is an inherited recessive disease that disrupts sphingomyelin lipid metabolism due to mutations in the SMPD1 gene. SMPD1 gen e codes for the enzyme acid sphingomyelinase (ASM). ASM degrades sphingomyelin in the lysosomal compartment of cells (Figure 1) (1). The loss of ASM activity in Niemann-Pick disease type A leads to abnormally high level of sphingomyelin to accumulate in cells throughout the body, disrupting their normal function. This typically results in death before 3 years of age (2). liver.jpg|Figure 3: Enlargement of liver seen at the age of 3 months in patients with Niemann-Pick diease Type A. Source: 23 and Me (7) Cherry-red-spot.jpg|Figure 4: Image of the eye showing a charateristic cherry red spot in the macula of the retina. This is seen in children with Niemann-Pick disease type A, usually after 12 months of age. Source: 23 and Me (7). Incidence Niemann-Pick disease type A is more commonly seen in Ashkenazi (eastern and central European) Jews. This is the only population wherein widespread DNA-based screening has taken place and the incidence rate is approximately 1 in 40,000 (3). The incidence statistics data for the general population is mainly based on the biochemical tests for enzymatic activity, rather than DNA sequence data. This data includes patients with Niemann-Pick disease type A and the other less frequent Niemann-Pick disease type B disease, together termed Acid Sphingomyelinase Deficiency. The estimated incidence rate based on these studies is about 0.5 to 1 per 100,000 births (4,5,6). Genotype and Phenotype The official name of the SMPD1 gene is 'sphingomyelin phosphodiesterase 1, acid lysosomal'. It is located on chromosome 11, between base 6,411,643 to 6,416,227. SMPD1's cytogenetic location is 11p15.4-p15.1 (Figure 2) (3). Mutations in the SMPD1 gene affect the enzymatic activity of ASM, which results in excess accumulation of the lipid sphingomylein in cells, leading to organ failure. This disease affects multiple organs and systematic loss of function can be seen. The first symptom seen usually by three months of age is enlargement of spleen and liver, which further increases with age (Figures 3 and 4) (7). Another classical phenotype is a cherry-red spot in the macula of the retina (Figure 4). Brain development takes place normally usually until age of one, but after that neurologic deterioration begins and does not stop. Excess storage of sphingomyelin the pulmonary macrophages leads lung infections and often lung failure. The multiple organ failures usually results in death before the age of three (8). There are more than 100 documented mutations that affect the ASM activity. The most widely seen mutations are shown in Figure 5 (9). DNA sequence data provides vital information showing if a person may be a carrier for the disease. This is particularly important because Niemann-Pick disease type A is a recessive autosomal disease. This means, loss of ASM enzyme activity is only seen if the individual has mutations in both alleles for the gene. A heterozygous carrier would not show any symptoms and will pass the diagnostic biochemical confirmatory test for the disease. If the other partner is also carrier of Niemann-Pick disease type A, the likelihood of the offspring getting the disease or not getting the disease and not being a carrier of the disease is 25% each. There is a 50% chance that the offspring will not get the disease and not be a carrier as well (Figure 6) (10). The company 23 and me have further picked the three most frequent mutations and provide the sequence for only these in their $99 package for sequence data. Diagnosis and Treatment Biochemical test for the enzyme activity for ASM is the widely used confirmatory test for the disease, apart from the DNA sequence analysis for mutations. The DNA analysis is helpful in the sense that it provides vital information showing if a person may be a carrier for Niemann-Pick disease type A. There is currently no treatment for Niemann-Pick disease type A. Attempts are made to control symptoms of patients to alleviate pain. Genetic counselling is recommended to carriers of the disease. Dr. John Burke's genome analysis for Niemann-Pick Type A Drr. John Burke does not have any mutation in any of the three sequence data provided by 23 and me. Although these are the three most common mutations seen in patients with Niemann pick type A, this data should be approached with caution, especially as most of the sequence data is from individuals of the Ashkenazi Jewish decent. And more importantly, Dr. Burke may still be a carrier for the disease and have a mutation in one of the regions whose sequence is not provided by 23 and me. This a concern as 23 and me provided sequence information for only 3 possible mutation from among more than a 100 possible mutations that could cause the disease. References 1. http://themedicalbiochemistrypage.org/niemannpickdiseases.php 2. Schuchman, E.H., The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inherit Metab Dis, 2007. 30(5): p. 654-63. http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&term=17632693 PubMed 3. http://ghr.nlm.nih.gov/gene/SMPD1 4. Meikle, P.J., et al., Prevalence of lysosomal storage disorders. JAMA, 1999. 281(3): p. 249-54. http://www.ncbi.nlm.nih.gov/pubmed/9918480 PubMed 5. Poorthuis, B.J., et al., The frequency of lysosomal storage diseases in The Netherlands. Hum Genet, 1999. 105(1-2): p. 151-6. http://www.ncbi.nlm.nih.gov/pubmed/10480370 PubMed 6. Pinto, R., et al., Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet, 2004. 12(2): p. 87-92. http://www.ncbi.nlm.nih.gov/pubmed/14685153 PubMed 7. 23 and Me 8. McGovern, M.M., et al., Natural history of Type A Niemann-Pick disease: possible endpoints for therapeutic trials. Neurology, 2006. 66(2): p. 228-32. http://www.ncbi.nlm.nih.gov/pubmed/16434659 PubMed 9. http://www.ncbi.nlm.nih.gov/books/NBK1370/#npab.REF.mcgovern.2006.228 10. http://www.medindia.net/patients/patientinfo/niemann-pick-disease.htm